Amidoxime derivatives, processes for the preparation

Abstract

The invention provides amidoxime derivatives of the general formula ##STR1## wherein R 1 is an alkyl group of 1 to 8 carbon atoms, phenyl, a heterocyclic ring structure of 5 to 8 atoms containing one or more nitrogen or oxygen atoms or combinations thereof or a bicyclic condensed ring system optionally containing at least one heterocyclic ring which groups may each be optionally substituted. R 2 is a mono or bicyclic heterocyclic radical containing at least two nitrogen atoms which radical is also optionally substituted. R 3 and R 4 are independently H, or an alkyl of 1 to 4 carbon atoms or one, but not both, is ##STR2## and the other, H, wherein R 5 or R 6 are alkyls of 2 to 5 carbon atoms optionally substituted by R 1 , or a phenyl optionally substituted by R 1 or R 5 or R 6 is combined with R 1 to jointly form cyclic imidoximes or imidedioximes. The invention also provides processes for the preparation of these compounds and many uses therefor including application in affinity chromatography, enzyme reactors and for preparing dense and porous fibers, fabrics and particles.

What is claimed is: 
     
       1. Compounds of the formula I ##STR57## wherein R 1  is H, an alkyl group of 1 to 8 carbon atoms, phenyl, a heterocyclic ring structure of 5 to 8 atoms containing one or more nitrogen or oxygen atoms or combinations thereof or a bicyclic condensed ring system optionally containing at least one heterocyclic ring as defined, which groups are optionally substituted by one or more halogen, amine, alkylamine, dialkylamine, amidoxime substituted alkylamine, hydroxy, alkoxy, nitroxide, branched and straight chain alkyl, nitro, cyano, carboxamide, carbonyl, carboxyl, sulphonamide, sulphonimide, phosphonyl, sulphonyl, oxime, amidoxime optionally substituted with a mono or bicyclic heterocyclic radical containing at least two nitrogen atoms which radical itself it optionally substituted by halogen groups; a polymeric radical of the structure ##STR58## wherein R 19  is attached to the carbon atom of formula 1 and is a valence bond, an alkyl group of 1 to 4 carbon atoms, a group of the formula --O--(CH 2 )- p  or --NH--(CH 2 )- p  where p is 1-6, or ##STR59## n 2  is 0 or a whole number defined by the polymers molecular weight and its relationship to n 1  defined by the ratio of n 2  to n 1 , which may take values from 0 to 20, the n 1  s and n 2  s are randomly distributed or distributed in blocks in the polymer backbone and M 1  and M 2  are olefins, wherein M 2  may be the same or different monomers such that M 1  and M 2  form co-, ter-, tetra- or penta-polymers or M 1  and M 2  are cellulosic or polysaccharides or M 1  and M 2  are polysulfones, polyphenyleneoxides, polyamides, or epoxy polymers, respectively, wherein the polymer molecular weight may vary from 200-5,000,000 or to such a molecular weight, considered infinite, as may be defined by a crosslinked solid or gel; R 2  is a mono or bicyclic heterocyclic radical of cyclic carbonic acid imide derivatives containing at least two nitrogen atoms, and optionally substituted alone or in combination with radicals of halogens, --NH 2 , mono and dialkyl amino of 1 to 6 carbons per alkyl chain, anilino, napthylamino, --OH, alkoxyl of 1 to 6 carbons, aryloxy; coloured and non-coloured tertiary amines, hydroxy, alkyl ammoniums of 1 to 6 carbons per alkyl chain, sulfonium, phosphonium and carboxylic, sulfonic and phosphonic acid derivatives of mono and dialkyl amino, anilino, naphthylamino, alkoxyl and aryloxy radicals; --SH, alkylthio of 1 to 6 carbon atoms, arylthio, hydrazine, --CN, phosphonic esters, --SO 2  HN 2 , arylsulfonamides, --SO 3  H, phenyl,alkyl (1 to 6 carbons); synthetic or biological oligomers and polymers, which are substituted in R 2  through amino (alkyl or aryl) groups, hydroxyl (alkyl or aryl), sulfhydryl groups or heterocyclic ##STR60## on the synthetic or biological oligomer or polymers, which R 2  groups themselves attached to an amidoxime on the same or different amidoxime polymers through R 19  ; amidoxime and diamidoxime groups which amidoxime groups themselves optionally are substituted by the hereinbefore defined substituents of R 1  and said diamidoxime groups are themselves optionally linked to a further R 2  group as hereinbefore defined forming an alternating polymeric structure of diamidoxime and R 2  groups; R 3  and R 4  independently H, or an alkyl of 1 to 4 carbon atoms or one, but not both, is ##STR61## and the other, H, wherein R 5  or R 6  are alkyls of 2 to 5 carbon atoms optionally substituted by R 1 , or a phenyl optionally substituted by R 1 , or R 6  and R 1  together form structures of the formula ##STR62## wherein R 2  is as defined and wherein R 2  ' is either R 2  or H, or wherein R 2  is H and R 4  is ##STR63## and R 5  and R 1  together form structures of the formula: ##STR64## wherein R 2  is as defined. 
     
     
       2. Compounds according to claim 1, wherein R 1  is an alkyl of 1 to 8 carbon atoms or a phenyl optionally substituted with halogens, or lower alkyls, and R 3  and R 4  are --H. 
     
     
       3. Compounds according to claim 1, wherein R 2  is a cyclic carbonic acid imide radical of a six membered ring containing at least two nitrogen atoms. 
     
     
       4. Compounds according to claim 1, wherein R 2  is a cyclic carbonic acid imide bicyclic condensed ring system containing at least one six membered ring of at least two nitrogen atoms. 
     
     
       5. Compounds according to claim 4, wherein R 2  is a halogen substituted quinoxaline. 
     
     
       6. Compounds according to claim 1, wherein R 2  is a 1,3,5-, 1,2,3- or 1,2,4-triazinyl, pyridazinyl, pyrimidyl, pyrazinyl, pyridazonyl, quinoxalinyl, phthalazinyl or quinazolinyl radical, optionally substituted with halogens, amino, --NHR 7 , NR 7  R 8  or --COOH, --CN, --CONH 2 , SO 2  NH 2 , --OR 10 , or SR 11  anilino groups, wherein R 7 , R 8 , R 10  and R 11  are independently H or alkyl chains with 1 to 8 carbons. 
     
     
       7. Compounds according to claim 6, wherein R 2  is a triazinyl or pyrimidal substituted by at least one halogen and optionally by an amino, --NHR 7 ,--NR 7  R 8 , anilino group. 
     
     
       8. Compounds according to claim 6, wherein R 2  is a triazinyl or pyrimidyl substituted by at least one halogen and optionally by a --OR 10  or --SR 11  group. 
     
     
       9. Compounds according to claim 3, wherein R 2  is a triazinyl or pyrimidal radical optionally substituted by at least one group selected from halogen, amines, alkylamines, arylamines, dialkylamines, quaternary ammonium, alkoxy and alkylthiol alkyl, carboxyl, cyano, carboxamide and sulfonamide groups. 
     
     
       10. Compounds according to claim 1, wherein the halogen atoms are F, Cl or Br. 
     
     
       11. Compounds according to claim 1, wherein R 2  is a 1,3,5-triazinyl or a pyrimidyl substituted by an additional amidoxime radical of the formula IV ##STR65## wherein R 22  independently has one of the values of R 1  and R 13  and R 14  are independently H or an alkyl of 1 to 4 carbon atoms. 
     
     
       12. Compounds according to claim 1, wherein R 1  is substituted with another radical of the formula V ##STR66## wherein R 15  independently has one of the values of R 1 , R 16  and R 17  are independently H or an alkyl of 1 to 4 carbon atoms and R 18  independently has one of the values of R 2 . 
     
     
       13. Polymeric compounds according to claim 12, wherein R 2  and optionally R 18  is substituted by at least two diamidoxime groups, which groups are themselves linked to further R 2  groups forming an alternating polymeric structure of diamidoxime and R 2  groups. 
     
     
       14. Polymeric compounds according to claim 13 formed from alternating diamidoxime and triazinyl or pyrimidyl radicals of the formula VI ##STR67## wherein R 1 , R 3 , R 4 , R 15 , R 16 , R 17 , and R 18  are as defined and n is a whole number of at least 2. 
     
     
       15. Polymeric compounds according to claim 1 of the formula IX ##STR68## where R 34  is H or an alkyl radical of 1 to 6 carbons, a phenyl or a halogen and R 31  and R 32  are independently radicals of H, halogens or an alkyl of 1 to 6 atoms and M 2  is one or more different monomers, which may be chosen individually or in combinations from polymerizable olefinic monomers, and the final molecular weight n 1  +n 2  may vary from 200 to 5,000,000 or to such a molecular weight considered infinite as defined by a crosslinked substance, and the ratio n 2  /n 1  varies from 0 to 20, wherein a fraction of the total number of R 12  's is substituted in part or solely with synthetic or biological oligomers or polymers through the primary or secondary alkylamines, arylamines, hydroxy alkyl, hydroxylaryl or sulfhydryl groups or heterocylic nitrogens of proteins, peptides, lectins, enzymes, hormones, polysaccharides, cellulosics, antibodies, antigens, polynucleotides, whole cells or cellular fragments, polyethylenimine, polyvinyl alcohol, polyvinylimidazole and poly(amino alkyl (meth) acrylates) with alkyls of 1 to 6 carbon atoms. 
     
     
       16. Compounds according to the polymeric structure of claims 1 and 15, wherein R 12  is substituted with reactive halogens. 
     
     
       17. Polymeric compounds according to claims 15 and 16, wherein M may be chosen from acrylonitrile, vinyl acetate, acrylic acid, methacrylic acid, allyl sulfonate, vinyl alcohol, styrene, allyl halide, or combinations thereof. 
     
     
       18. Compounds according to claims 15 and 16, wherein M 2  is acrylonitrile or acrylonitrile and another copolymer is defined, R 19  is a valence bond, R 13  and R 14  are H, and R 12  is a substituted triazinyl or pyrimidyl radical as defined. 
     
     
       19. Crosslinked compounds according to claims 16, 17 and 18, wherein R 12  is a triazinyl or pyrimidyl radical substituted with reactive halogens. 
     
     
       20. Crosslinked structures according to claims 15, 16, 17 and 18, wherein R 12  is substituted in part by biological molecules chosen from enzymes, hormones, peptides, lectins, polysaccharides, proteins, antibodies, antigens, or proteins, and optionally substituted in the same or different R 12  with the other groups cited in claim 1. 
     
     
       21. Compounds according to claims 15, 17 and 18, wherein R 2  is substituted with polyethylimine (PEI) or polyvinyl alcohol (PVA) of a molecular weight between 200 and 200,000 and said PEI or PVA molecule is optionally bound to more than one R 2  radical. 
     
     
       22. Crosslinked structures according to claims 15 to 21 in the form of particles, fibers or sheets, all of which are either porous or non-porous. 
     
     
       23. Compounds accorsing to the polymeric structures in claims 1 and 15, wherein R 12  is a radical derived from reactive dyes or colourless radicals derived from carbonic imide halides containing one or more of the following ionic groups-sulfonic and phosphoric; carboxyl (all in the acid or salt form), quaternary ammoniums, phosphonium or sulfoniums. 
     
     
       24. Compounds according to claims 15, 16, 17, 21, and 22, wherein R 12  is a reactive dye or colourless radical based on triazinyl, pyrimidyl, quinoxaline-6-carbonyl, pyridazonly, propionyl, 1,4-dichloro-phthalazine-6-carbonyl or benzothiazole. 
     
     
       25. Compounds according to claim 1, wherein R 3  is H and R 4  is ##STR69## and R 6  together with R 1  form structures of the formula ##STR70## in which R 2  ' is H or R 2 . 
     
     
       26. Compounds according to claim 25, wherein R 2  is a substituted triazinyl, pyrimidyl or quinoxaline radical as defined. 
     
     
       27. Compounds according to claim 1, wherein R 3  is H, R 4  is ##STR71## and R 5  together with R 1  form structures of the formula ##STR72## 
     
     
       28. Compounds according to claim 27, where R 2  is a substituted triazinyl, pyrimidyl or quinoxaline radical as defined. 
     
     
       29. Compounds according to claim 1, having the structure VIII: ##STR73## wherein each R 2  ' is independently either R 2  or H, R 2  is a triazinyl or pyrimidyl radical and Q is 2, 3 or 6. 
     
     
       30. A process for the manufacturing of compounds of claim 1 comprising reacting an amidoxime of the structure: ##STR74## with a compound of the formula R 2  -Hal, wherein R 1 , R 2 , R 3  and R 4  are as defined in claim 1 to form a compound of the formula I ##STR75## 
     
     
       31. A process according to claim 30, wherein R 2  is selected from the group consisting of a 1,3,5-, 1,2,3-, 1,2,4-triazinyl, pyridazinyl, pyrimidyl, pyrazinyl, pyridazonyl, quinoxalinyl, phthalazinyl or quinazolinyl radical, optionally substituted with additional halogen, --COOH, --CN, --CONH 2 , anilino-, --SO 2  NH 2 , --NR 7  R 8  R 9 , --OR 10 , or --SR 11  groups, wherein R 7 , R 8 , R 10  and R 11  are independently H or alkyl chains with 1 to 8 carbons. 
     
     
       32. A process according to claim 30, wherein R 2  -Hal is cyanuric chloride, tetrachloropyrimidine or a mono- or di- substituted derivative thereof, wherein said substitutents are selected from the group consisting of amine, hydroxy, alkylamines, hydroxy alkylamines, alkoxy or alkylthiol groups, wherein said alkyl groups contains 1 to 4 carbon atoms. 
     
     
       33. A process according to claim 30 comprising reacting a diamidoxime of the formula X ##STR76## with a compound of the formula R 2  -Hal, wherein R is a phenyl group optionally substituted by at least one halogen group, or a radical of the formula --CH 2  -- n  and n=1 or 8. 
     
     
       34. A process for manufacturing a polymeric compound as defined in claim 14 comprising reacting a diamidoxime with a compound of the formula R 2  -Hal, wherein R 2  -Hal contains at least two reactive halogen group. 
     
     
       35. A process according to claim 34, wherein R 2  -Hal is cyanuric chloride or tetrachloropyrimidine. 
     
     
       36. A process for manufacturing a polymeric compound as defined in claims 1 and 15 comprising reacting a polymer containing nitrile groups with a hydroxylamine and then subsequently reacting the product thereof with R 2  -Hal. 
     
     
       37. A process according to claim 36, wherein R 2  -Hal is cyanuric chloride or tetrachloropyrimidine, or a substituted R 2  -Hal of cyanuric chloride or tetrachloropyrimidine, wherein the substituted is a low molecular radical defined in claim 1. 
     
     
       38. A process according to claims 36 and 37, wherein the nitrile containing polymer is polyacrylonitrile or a copolymer of polyacrylonitrile with a vinylacetate, acrylic acid, styrene, methacrylic acid, allyl bromide, acrylic acid or allyl sulfonate. 
     
     
       39. A process according to claims 36, 37 and 38 comprising the further step of reacting a water soluble polymer containing amino or hydroxyl groups with unreacted halogen substituents of the R 12  radical of compounds of formulas 1a & IX. 
     
     
       40. A process according to claim 39, wherein the water soluble polymer is polyethyleneimine, polyvinyl alcohol, polyvinylamine, or water soluble polysaccharides. 
     
     
       41. A process according to claims 36, 37 and 38 comprising the further step of reacting an enzyme with unreacted halogen substituents of the R 12  radical of compounds of formulas 1a and IX. 
     
     
       42. A process according to claims 36 and 37 comprising the further step of reacting a lectin, a hormone, an amino acid, a polypeptide, an antibody, an antigen, a whole cell or cellular fragments with unreacted halogen substituents of the R 2  radical of compounds of formulas I, Ia and IX. 
     
     
       43. A process according to claims 36 and 37, wherein the R 2  -Hal compound is reacted with the polyamidoxime polymer under conditions whereby the polymeric material is crosslinked and 0.1 to 3.0 meq of reactive halogen of R 2  -Hal for each gram of dried polymer or left as substituents of R 2  unreacted. 
     
     
       44. A process according to claims 39 through 43, wherein the polymer is in the form of a porous or non-porous particles, fibers, cloth or films. 
     
     
       45. A process according to claims 36, 41 and 42, wherein R 2  -Hal is a reactive dye based on symmetrical and unsymmetrical triazines and diazines. 
     
     
       46. A process according to claim 44, wherein the original nitrile polymer is in the form of a fiber 1μ to 1 mm in diameter, a fabric or net of such fibers or a particle 0.1μ to 5 mm in diameter, wherein the material is porous or nonporous. 
     
     
       47. A process according to claims 43 through 46, wherein R 2  -Hal is a reactive dye based on symmetrical and unsymmetrical triazines and diazines and the particle, fiber or fabric is dyed by the process. 
     
     
       48. A process according to claims 43 through 45 comprising the further step of reacting a water soluble polymer containing amino or hydroxyl groups with unreacted halogen substituents of the R 12  radical of compounds of formula IX, wherein the net, fiber, fabric or particle is made hydrophilic. 
     
     
       49. A process according to claims 43 and 44 comprising the further step of reacting an enzyme with unreacted halogen substituents of the R 12  radical of compounds of formula Ia and IX. 
     
     
       50. A process according to claims 43 and 44 comprising the further step of reacting a lectin, a hormone, an amino acid, a polypeptide, an antibody, an antigen, a whole cell or cellular fragments with unreacted halogen substituents of the R 12  radical of compounds of formulas Ia and IX. 
     
     
       51. A process according to claim 48, wherein the product is used in an enzyme reactor. 
     
     
       52. A process according to claim 49, wherein the product is used in an affinity chromatography column.